The goal of this project is twofold. First, we seek to study the impact of acyl chain structures typically found in bacterial lipids on antimicrobial peptide activity. Second, we will determine if acylation of an antimicrobial peptide with specific lipid structures will yield a more efficient antimicrobial agent while maintaining a high therapeutic index. To this date, most studies on the interaction of antimicrobial peptides with model bilayer systems have focused on readily available lipids that exist in only negligible quantities or not at all in cell membranes of many bacteria that represent a health threat to humans. We suggest that this approach has oversimplified the complex bacterial cell membrane and that the acyl chain structure of bacterial lipids plays a crucial role in the sensitivity of bacteria to antimicrobial peptides. We will test this hypothesis by studying peptide-membrane interactions in model systems using bacterial lipids of both natural and synthetic origin, and in bacterial cultures. We further suggest that the efficacy of antimicrobial peptides can be enhanced by the addition of a lipid anchor that, depending on its structure, facilitates peptide-induced membrane perturbation. Understanding the significance of lipids found in a variety of bacteria will help us to overcome bacterial adaptations to current antibiotics and to design new strategies of how to efficiently combat pathogenic bacteria. 1 PUBLIC HEALTH RELEVANCE: Bacterial resistance to conventional antibiotics is on the rise. Antimicrobial peptides are usually the first line of defense against invading microorganisms in most organisms, including humans. This project seeks to study the role of unique bacterial lipid structures in bacterial sensitivity to antimicrobial peptides and to develop new design strategies for novel antibiotics.